The detection of new tumors or the recurrence of tumors remains an unfulfilled goal of humankind, despite enormous expenditures of both financial and human resources over the last twenty-five plus years. A number of cancers are treatable if detected at an early stage, but unfortunately go undetected in many patients for lack of a reliable screening procedure. For illustrative purposes, background for a particular cancer, bladder cancer, is described in more detail and is representative of cancers in need of new approaches, which the invention disclosed herein provides.
Bladder cancer is the fifth most common cancer in the United States. The American Cancer Society estimated that a total of 52,000 new cases would be detected in 1994 and that there would be 10,000 deaths resulting from this disease. Bladder cancer is more common in men than in women by a ratio of approximately three to one and has been shown to be highly associated with smoking as well as exposure to certain dyes. Carcinoma of the urinary bladder is the fourth most common malignancy among American men, and the eighth among women. Transitional cell carcinoma (TCC) is the most common type of bladder cancer representing greater than 90% of all cases. The remaining cases are squamous cell carcinomas (7%), adenocarcinomas (2%), and undifferentiated carcinomas (1%).
The diagnosis and management of TCC is often performed as follows. The patient presenting with such symptoms as hematuria or dysuria in the absence of infection undergoes a cystoscopy at which time the tumor is visualized. Although this procedure is invasive and unpleasant, it is highly accurate in predicting malignancy and is, thus, considered the gold standard. Urine cytology (i.e., the identification of tumor cells in voided urine) is also performed, and the combined results of the two methods may lead to an increase in sensitivity over that of cystoscopy alone. This is due to the fact that cytology occasionally allows detection of tumors which are not visible during cystoscopy, for example, flat tumors of the bladder (TIS) or those in the upper end of the bladder or the upper urinary tract.
Transurethral biopsy and resection are then usually performed with this procedure removing the apparent lesion as well as providing information as to the grade and stage of the tumor. The tumor is typically graded from G0 to G4 in decreasing state of differentiation. As with most cancers, the less differentiated the tumor the more aggressive the disease. With respect to stage or extent of invasion, TCC's of the bladder may be classified as superficial papillary (Ta and T1), muscle invasive (T2 and greater), or the relatively uncommon tumor in situ (TIS). The extent of invasion dictates the type of therapeutic approach employed and the follow-up procedures to monitor for disease recurrence.
Individuals with invasive TCC (Stage T2, T3, and T4) typically have poor prognoses. They are usually treated by radical cystectomy; however, in some cases the patient is unable to tolerate this surgery and is treated by radiation therapy or chemotherapy instead. This latter subgroup is monitored for disease recurrence by cystoscopy and urine cytology.
Approximately 75% of TCC patients are initially diagnosed as having either Ta or T1 disease. In part because bladder cancer is multifocal, initial resection and treatment of these patients is curative in less than half of the cases. Although patients presenting with Ta TCC usually recur, their tumors tend to be low grade, and only 10-15% of the tumors will progress to muscle invasive disease. In contrast, T1 patients will progress 30-50% of the time. Superficial TCC is usually treated by transurethral resection, intravesical therapy, or fulguration, and follow-up is usually by cystoscopy and voided urine cytology.
As mentioned above, current practice includes a preliminary diagnosis of TCC by cystoscopy and urine cytology, confirmatory diagnosis and staging and grading by biopsy, and routine follow-up of superficial and some invasive TCC by cystoscopy and urine cytology. Recurrence, especially within the first 12 months, is common, even when tumors have been diagnosed and treated prior to invasion of the bladder muscle. Therefore, patients with superficial TCC are typically monitored every three months for the first two years and, if there is no recurrence, every six months during the following year. Because cystoscopy is invasive and unpleasant and because urine cytology, although highly specific, is of variable reliability in detecting recurrence, there is a significant need for alternative diagnostic approaches.
Accordingly, there is a need in the art for a non-invasive diagnostic method with reliability in detecting occurrence or recurrence. The present invention fulfills this need and further provides other related advantages.